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First Fully Functional Yeast Chromosome Synthetically Designed

An international team of scientists reports the synthesis of the first functional chromosome in yeast. They point out that this marks an important step in the emerging field of synthetic biology, designing microorganisms to produce novel medicines, raw materials for food, and biofuels.

Over the last five years, scientists have built bacterial chromosomes and viral DNA, but this is the first report of an entire eukaryotic chromosome built from scratch. “Our research moves the needle in synthetic biology from theory to reality,” says Jef Boeke, Ph.D., director of the NYU Langone Medical Center’s Institute for Systems Genetics. “This work represents the biggest step yet in an international effort to construct the full genome of synthetic yeast.”

According to Dr. Boeke, the yeast chromosome is the most extensively altered one ever built. But the milestone that really counts is integrating it into a living yeast cell. “We have shown that yeast cells carrying this synthetic chromosome are remarkably normal. They behave almost identically to wild yeast cells, only they now possess new capabilities and can do things that wild yeast cannot,” he noted.

In this week’s issue of Science online, the team’s study (“Total Synthesis of a Functional Designer Eukaryotic Chromosome”) describes how the researchers, using computer-aided design, built a fully functioning chromosome, which they call synIII, and successfully incorporated it into brewer’s yeast (Saccharomyces cerevisiae).

“We report the synthesis of a functional 272,871–base pair designer eukaryotic chromosome, synIII, which is based on the 316,617–base pair native Saccharomyces cerevisiae chromosome III. Changes to synIII include TAG/TAA stop-codon replacements, deletion of subtelomeric regions, introns, transfer RNAs, transposons, and silent mating loci as well as insertion of loxPsym sites to enable genome scrambling,” write the investigators. “SynIII is functional in S. cerevisiae. Scrambling of the chromosome in a heterozygous diploid reveals a large increase in a-mater derivatives resulting from loss of the MATα allele on synIII. The complete design and synthesis of synIII establishes S. cerevisiae as the basis for designer eukaryotic genome biology.”

“When you change the genome you’re gambling. One wrong change can kill the cell,” continued Dr. Boeke. “We have made over 50,000 changes to the DNA code in the chromosome and our yeast still live. That is remarkable. It shows that our synthetic chromosome is hardy, and it endows the yeast with new properties.”

The effort was aided by some 60 undergraduate students enrolled in the “Build a Genome” project, founded by Dr. Boeke when he was at Johns Hopkins. The students pieced together short snippets of the synthetic DNA into stretches of 750 to 1,000 base pairs or more, an effort led by Srinivasan Chandrasegaran, Ph.D., a professor at Johns Hopkins, who is also the senior investigator of the team’s studies on synIII.

Student participation kicked off what has become an international effort, called Sc2.0 for short, in which several academic researchers have partnered to reconstruct the entire yeast genome, including collaborators at universities in China, Australia, Singapore, the U.K., and elsewhere in the U.S.

Yeast chromosome III was selected for synthesis because it is among the smallest of the 16 yeast chromosomes and controls how yeast cells mate and undergo genetic change. Yeast shares roughly a third of its 6,000 genes—functional units of chromosomal DNA for encoding proteins—with humans. The team was able to manipulate large sections of yeast DNA without compromising chromosomal viability and function using a so-called scrambling technique that allowed the scientists to shuffle genes like a deck of cards, where each gene is a card.

“We can pull together any group of cards, shuffle the order, and make millions and millions of different decks, all in one small tube of yeast,” noted Dr. Boeke. “Now that we can shuffle the genomic deck, it will allow us to ask, can we make a deck of cards with a better hand for making yeast survive under any of a multitude of conditions, such as tolerating higher alcohol levels.”

Using the scrambling technique, researchers say they will be able to more quickly develop synthetic strains of yeast that could be used in the manufacture of rare medicines, such as artemisinin for malaria, or in the production of certain vaccines, including the vaccine for hepatitis B, which is derived from yeast. Synthetic yeast, they say, could also be used to bolster development of more efficient biofuels, such as alcohol, butanol, and biodiesel.

The study will also likely spur laboratory investigations into specific gene function and interactions between genes, added Dr. Boeke, in an effort to understand how whole networks of genes specify individual biological behaviors.

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